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M. Zhao
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OA 18 - Lung Cancer Pathology and Genetics (ID 687)
- Event: WCLC 2017
- Type: Oral
- Track: Biology/Pathology
- Presentations: 1
- Moderators:George R. Simon, Yoon-La Choi
- Coordinates: 10/18/2017, 14:30 - 16:15, Room 316
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OA 18.01 - Paired Tumor-Normal Next-Generation Sequencing (NGS) to Identify Pathogenic / Likely Pathogenic Germline Mutations in Lung Cancer Patients (ID 10326)
14:30 - 14:40 | Author(s): M. Zhao
- Abstract
- Presentation
Background:
Comprehensive NGS panel based genetic testing is becoming more common to help clinicians select appropriate therapies. It has been recommended that matched tumor-normal sequencing analyses are essential for precise identification and interpretation of genetic somatic mutations. Though it has been reported germline EGFR T790M mutations result in a unique hereditary lung cancer syndrome, little is known about germline mutation of other common hereditary cancer syndrome genes in lung cancer patients.
Method:
We reviewed the germline variants of 1000 consecutive lung cancer patients who had paired tumor-normal NGS panel sequencing in our institute between 2016 and 2017. Hybridization capture-based NGS panel sequencing enables simultaneously assess single-nucleotide variants, insertions/deletions, rearrangements, and copy-number alterations at least 59 genes (range 59 – 1021 genes). Germline variants were interpreted following ACMG guidelines, and the variants were classified into pathogenic, likely pathogenic, variant of unknown significance, likely benign, and benign 5 classes.
Result:
Twenty-seven cases were identified to carry germline pathogenic or likely pathogenic mutations in 12 gene (2.7%): 5 with ATM ; 4 with BRCA1, BRCA2 or MSH2 respectively; 2 with CHEK2 or PMS2 respectively; 1 in ATR, CDKN2A, FANCC, MSH3, PTCH2 or RET respectively (details in table). Mean age at diagnosis was 58 (30 – 84 years) for the patients with germline mutations and 61 (29-93 years) for those without. Interestingly, none of the patients had been diagnosed with other tumors. The incidence of actionable somatic mutations of the 27 patients was similar to others: 10 patients with EGFR mutation, 3 patients with KRAS mutation, 1 patient with KIF5B-RET fusion, MET copy number gain or BRCA1 mutation respectively.No. Gene cHGVS pHGVS Mutation type 1 ATM c.1402_1403delAA p.K468Efs*18 frameshift 2 ATM c.1898+1G>C . splice 3 ATM c.2143_2144delCT p.L715Cfs*22 frameshift 4 ATM c.6019dupG p.E2007Gfs*11 frameshift 5 ATM c.903dupT p.A302Cfs*3 frameshift 6 ATR c.80_81insA p.N27Kfs*16 frameshift 7 BRCA1 c.4185+1G>A . splice 8 BRCA1 c.962G>A p.W321* nonsense 9 BRCA1 c.3340delG p.E1114Kfs*3 frameshift 10 BRCA1 c.81-2A>G . splice 11 BRCA2 c.3968_3971delAATA p.K1323Ifs*11 frameshift 12 BRCA2 c.5054C>G p.S1685* nonsense 13 BRCA2 c.6132_6135delCTTT p.F2045Hfs*5 frameshift 14 BRCA2 c.6485_6486delAA p.K2162Tfs*13 frameshift 15 CDKN2A c.73delG p.V25* frameshift 16 CHEK2 c.1010delC p.A337Efs*10 frameshift 17 CHEK2 c.1684C>T p.R562* nonsense 18 FANCC c.1257_1258insC p.T420Hfs*15 frameshift 19 MSH2 c.1165C>T p.R389* nonsense 20 MSH2 c.1A>T p.0? init-loss 21 MSH2 c.2785C>T p.R929* nonsense 22 MSH2 c.340delG p.E114Rfs*60 frameshift 23 MSH3 c.802C>T p.R268* nonsense 24 PMS2 c.1053delG p.L351Ffs*5 frameshift 25 PMS2 c.943C>T p.R315* nonsense 26 PTCH2 c.2441_2442delCT p.S814* frameshift 27 RET c.2410G>A p.V804M missense
Conclusion:
Germline mutations in common hereditary cancer syndrome genes is not rare in lung cancer patients, and it can be identified on routine matched tumor-normal NGS sequencing. Retrospective family history analysis and genetic counseling for those patients are underway.
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